As with other areas of molecular medicine, the study of underlying causes for MRDD has reached a level of complexity that will require powerful new tools to identify gene families, to map their coordinated expression and to understand how regulatory mechanisms are disrupted by disease. In the continuing commitment to support the investigators of the MRDDRC, the Molecular Genetics Core Facility has expanded its equipment and services to include those that will make the complex studies described above feasible. We have fine-tuned our other services so that they are routine, cost-effective and highly successful with rapid turnaround times. We will now focus on implementing new technologies, including high-throughput genotyping and microarrays to facilitate the study of gene expression patterns in normal and affected individuals. Some genetic diseases occur as the result of changes in DNA sequence or larger regions of genes or chromosomes, leading to missing or abnormal functioning of proteins and other gene products. However, some diseases may result from normal gene products that are expressed at abnormal levels, at inappropriate times in cell development or other more subtle aberrations. A promising approach to discovering how genes function and interact to produce normal and disease states is comparison of mRNA profiles from normal and abnormal cells or from cells at different stages of development. The altered pattern of expression that is observed may lead to identification of the roles of certain genes or could even be diagnostic for a particular disease. Ultimately the understanding of these gene systems may lead to more specific rationale-based therapies for a given disease. Parallel analyses of expression profiles on microdevices facilitates gene expression studies in several ways. First, the analysis of the complex population of cellular RNAs is well suited to the highthroughput parallel approach that microarrays provide. Such microdevices would also make efficient use of the limited amount of precious RNA isolated from cells as well as of the specialized reagents for amplification and detection. The increase in throughput and sensitivity combined with decreased cost per sample should make it possible to conduct experiments which will maximize the likelihood of detecting changes in these profiles while permitting numerous manipulations of variables and treatments. In addition to expression profiling, microarrays can be used to screen for one or numerous mutations in many individuals, determination of gene copy number and gene mapping studies. Quantitative PCR will also have a variety of applications to the projects in the Center, including relative and absolute transcript analysis and mutation detection.